Influenza A viruses exhibit extreme diversity as exemplified by the multiple serotypes of the hemagglutinin (HA, H1-H18) and neuraminidase (NA, N1-N11) surface antigens. To date, only three of the possible 198 combinations of HA and NA in avian and other animal reservoirs have been associated with human pandemics (H1N1, H2N2, H3N2). However, ever increasing anxiety about pandemic threats stemming from influenza viruses of zoonotic origins have heightened concern about emergence of a human transmissible virus that could devastate the human population. The recent appearance of H5N1, H6N1, H7N7, H7N9, H9N2, and H10N8 viruses in the human population are constant reminders of this possibility. Influenza B viruses with their two distinct lineages further increase the health and economic burden of seasonal influenza worldwide. In this proposal, we aim to elucidate, at the structural level, key sites of vulnerability on influenza virus and incorporate the essential information on how antibodies and receptor analogs target these sites into structure- based design, development, and synthesis of novel therapeutics. Antibody-mediated neutralization of influenza virus is a complex combinatorial problem for the human immune system when presented with diverse, highly variable and constantly evolving viruses. While neutralizing antibodies against human flu are traditionally regarded as being strain specific, recent advances have shown that much broader responses can be mounted and provided us with valuable new insights into conserved sites of vulnerability. We are amassing compelling evidence that a sustained, cross-serotype response can be mounted against influenza and this vital information can now be harnessed for design of small molecules, peptides, and proteins to target these key sites of vulnerability, thereby blocking influenza infection. No effective drugs are currently available for preventing entry of influenza virus. As a proof-of-concept of our approach, we have determined the crystal structure of umifenovir (an antiviral for influenza infection used in Russia and China) in complex with HA and exploited this structural information to synthesize a derivative with 100x improved binding. We will elucidate common features for recognition of these sites of vulnerability in pandemic and emerging influenza viruses from crystal structures of diverse HAs with broadly neutralizing antibodies as well as sialosides that are mimics of the natural receptor. A combined biophysical, biochemical, and chemical approach employing state-of-the- art structural biology, yeast-display evolution, and chemical biology will be harnessed to design and synthesize small molecules as novel therapeutic candidates to control and combat the threat of future influenza pandemics as well as seasonal epidemics.